Scientists Still Hopeful About Gene Therapy's Promise
by Joe Palca
March 8, 2010 www.npr.org
Twenty-five years ago, it seemed as if gene therapy was on the verge of revolutionizing medicine. But that revolution never occurred, and scientists realized that they had been overly optimistic about how quickly they could develop such therapies.
Now, however, there are signs that the field of gene therapy is making definite progress, even if the revolution is still on hold.
The concept of gene therapy is simple. Some diseases are caused by damage to a single gene — for example, cystic fibrosis and hemophilia. Give patients the healthy gene, and in theory, the disease is cured.
From Radical To Reliable: The Rise Of A Medical Treatment
First described as a cancer treatment in the Sept. 12, 1957, issue of the New England Journal of Medicine, bone marrow transplantation did not achieve widespread acceptance until the 1990s. Experts say that gene therapy is on a similar track, and the treatment is on the verge of taking off clinically, much like bone marrow transplantation did in the early 1980s.
Chart: Bone marrow transplants worldwide per year, 1957-2005
Source: Appelbaum F. N Engl J Med 2007;357:1472-1475
Credit: Alyson Hurt and Jason Orfanon / NPR
Dr. Mark Kay, who now runs the gene therapy program at Stanford University, says that in the early days of gene therapy, it turned out to be extremely difficult to get healthy genes into the cells that needed them.
"If we saw one cell out of a million, or even 10 million or 100 million, that were genetically modified with the gene therapeutic, we would be excited," he says. How Gene Therapy Works
It's no simple job to get genes into individual cells, but there is one organism that is extremely good at it: a virus.
"What a virus does is deliver its own genetic material to a cell," says Ken Cornetta, president of the American Society of Gene and Cell Therapy.
A technician collects re-engineered viruses, called “vectors.”
Paul Sakuma/AP
A technician at Avigen Inc., a company pursuing cures based on gene and cell therapy, collects re-engineered viruses, called "vectors." Viruses, stripped of their virulence and ability to replicate, are the most common delivery vehicles for healthy DNA.
Inside A Gene Therapy Breakthrough
With one injection of an experimental gene therapy treatment, doctors have significantly improved the sight of people born with a rare congenital vision disorder . Science Friday: Gene Therapy And Blindness
"What we can do in the setting of gene therapy is to re-engineer that virus to allow it to do what it does best, which is deliver genetic material to a cell. But we can also remove the viral genes, and replace them with the genes that we need to deliver to the cell to treat the disease," he says.
But there were problems. When scientists used viruses to insert genes into patients, their immune systems tried to fight off the virus. And then, when the genes did get in, in some cases they switched on other genes that caused cancer, making the cure nearly as bad as the disease.
"The field was in big trouble 10 years ago, says Joseph Glorioso, a researcher and editor of the journal Gene Therapy. "A lot of people were disillusioned — 'Oh this is never going to work, we thought it would be easy,' and all that."
But Glorioso says gene therapists are a stubborn bunch, and despite the setbacks, many researchers kept at it. He says many therapies take a long time to make it from the lab bench to the bedside.
Take bone marrow transplants. They were first attempted in the 1950s, but it wasn't until the 1980s that they began to be used routinely to treat leukemia and other blood disorders. A Reason To Be Optimistic
The field of gene therapy is now seeing positive results. Scientists have found new ways to modify viruses to make them better at delivering genes, and several studies are showing that the gene therapy can effectively treat an array of disorders.
There's a therapy for a rare immune disorder called ADA deficiency, and more recently scientists at the Children's Hospital of Philadelphia reported dramatic success using gene therapy to treat a rare inherited form of blindness. It was a small study — only 12 subjects.
"All of the subjects showed improvement," says Kathy High, a Howard Hughes Medical Institute investigator and one of the leaders of the study. She says the improvement was greatest for the children in the study.
High says we should expect to hear more success stories in the coming months and years — and not just for rare disorders, but for more common diseases like AIDS and cancer.
"I really do think that the field, you know, after a long labor, is beginning to deliver," says High. "It's a nice time to be working in this field."
Maybe now, scientists' optimism is justified
Rare Disease Treated Using Gene Therapy
by Joe Palcawww.npr.org
text sizeAAANovember 5, 2009
Researchers in France have successfully treated two young boys with a rare but fatal genetic disease. This marks a high point for the field of gene therapy after several well-publicized setbacks.
comparison scan of brain
EnlargeImage courtesy of Science/AAAS
Brain scans of two boys with ALD. The scans on the left (A) are from a patient who received gene therapy; the one on the right (B) did not. The white areas represent the brain damage caused by the disease. The arrow on the left points to an area that showed some damage, but receded over the course of the therapy. Click on the image to see how the brains progressed over time.
comparison scan of brain
Image courtesy of Science/AAAS
Brain scans of two boys with ALD. The scans on the left (A) are from a patient who received gene therapy; the one on the right (B) did not. The white areas represent the brain damage caused by the disease. The arrow on the left points to an area that showed some damage, but receded over the course of the therapy. Click on the image to see how the brains progressed over time.
Patrick Aubourg leads the French research team. Since 1993, he's been working on a disease called X-linked adrenoleukodystrophy — or ALD. ALD is a devastating neurological disease, incapacitating and ultimately killing people who have it. Many people became familiar with ALD from the 1992 movie Lorenzo's Oil, which featured a young boy affected with this disease. Viral Vectors
Since ALD is caused by a single gene, it's an ideal candidate for gene therapy. Put the repaired gene back into patient's cells, and that should fix the problem.
Simple in theory, but in practice, it's been extremely difficult. The biggest hurdle has been finding an efficient way to get the repaired gene into the cells of patients. One of the tricks involves attaching the gene to a virus. The virus acts as a vector, inserting the repaired gene into cells.
But the viral vectors can cause their own problems. In one case, another team of French researchers successfully treated several patients with a different single-gene disease, only to find that the vector caused some of the patients to develop leukemia.
Aubourg thinks he has now found a safer virus, and after treating two patients, the results are promising. As he and colleagues report in the Nov. 6 edition of Science, two patients have now been successfully treated.
"I use the term 'treated,' " says Aubourg. "I don't use the term 'cure' — treated. The disease has been arrested, not reversed, really."
But arresting the disease may be enough if the treatment is done before the disease progresses too far.
David Williams of Children's Hospital Boston says Aubourg's technique for getting the repaired gene into a patient's cells is the most efficient yet reported. But it's still not all that efficient.
"They have about 10 to 20 percent of the cells carry the new gene," says Williams. But, he adds, "that's enough, it appears, to arrest the progression of the disease." Safety Issues
Williams also thinks Aubourg's new viral vector will be safer than others used in the past. Aubourg does not report any problems associated with the vector in his Science paper.
"Having said that, these patients are still only three years or so out from their therapy," says Williams. "So it's still possible that something would evolve, although there's no indication in the molecular analysis that it would evolve."
Other researchers are impressed with the French team's results. Jude Samulski, director of the gene therapy center at the University of North Carolina, says it should change the way ALD is treated.
"It's going to start a flurry of activity," says Samulski. Even though it's a rare disease, he says that at the University of North Carolina, they see a lot of kids with the disease. "And now that we know there's an approach that might work, we'll start trying it. Because if they can't get a bone marrow transplant, they've got nothing."
Bone marrow transplants have been shown to work with ALD patients, but the transplants are risky, and frequently there's no donor available. Gene Therapy's Coming-Of-Age
Williams says the French results may mean gene therapy is finally coming of age.
"When gene therapy started, there were a lot of predictions that this was going to revolutionize medicine. It's been a long time to actually get it to work in humans"
If the treatment for ALD holds up, it might be the start of that revolution
Dalton, who was treated for red-green color blindness, enjoys a feast
EnlargeNeitz Laboratory
Dalton, a squirrel monkey, had gene therapy to correct his colorblindness. The image on the left is digitally altered to simulate what the scene would look like to a person (or monkey) with red-green color blindness. September 17, 2009
Scientists have used gene therapy to achieve full color vision in two squirrel monkeys that were born unable to tell red from green.
The technique could someday be used on people with colorblindness or other vision problems. All Male Squirrel Monkeys Are Colorblind
The monkeys, named Sam and Dalton, could see only blue and yellow before they were treated.
All male squirrel monkeys are born with this type of color blindness. They lack a receptor in their eyes that would let them see red and green. Female squirrel monkeys do have the receptor and can see the whole spectrum.
Researchers at the University of Washington developed a gene therapy technique to reprogram some of the color receptors in the male monkeys' eyes.
But many scientists were skeptical about the approach, says Jay Neitz, a University of Washington professor of ophthalmology.
"I went out and asked all my neuroscientist friends, 'If I do this in an adult monkey, will this give them color vision?' " Neitz says. "And everyone said, 'Absolutely not.' "
Dalton takes the color vision test. The monkey was trained to find blobs of color hidden in a patte
EnlargeNeitz Laboratory
Dalton takes the color vision test. The monkey was trained to find blobs of color hidden in a pattern of dots. He was given a drop of juice every time he got the correct answer. Reprogramming Color Receptors
The scientists told Neitz that even if the new receptors worked properly, it was unlikely that the monkeys' new eyes would be able to communicate with their old brains. There would be no pathway to carry the information about red and green to the brain, or any circuitry to process it.
Neitz and his team tried the experiment anyway.
Dalton — named after John Dalton, the British scientist who originally described colorblindness — got treated first.
For several months, there was no change. Every day, Dalton tried to win an extra juice reward by searching for a red or green target on a computer screen. And every day he failed.
As time passed, Neitz says he got anxious. But he wasn't surprised. Previous experiments had shown that it took about five months to reprogram a critical mass of receptor cells. Remarkable Results
Then, at just about the five-month mark, Dalton started hitting the target every time.
"At first we told ourselves, 'You know, maybe he's just guessing really well today or something,' " Neitz says. "But over a few days, it became clear that he wasn't guessing. That floored us."
Later on, the other squirrel monkey, Sam, would have a similar epiphany.
Neitz says both monkeys have seemed pretty pleased with themselves ever since.
"It's just like a kid that goes in, and they don't want to get wrong answers on a test," he says. "They're very happy to be straight-A students now.
Scientists who study color vision are calling the story of Sam and Dalton, which appears in the journal Nature, "dazzling" and "surprising." Retraining An Adult Brain
Gerald Jacobs, a research professor at the University of California, Santa Barbara, says it's remarkable that the technique worked at all on an adult animal.
Earlier research had shown that, after childhood, the brain loses much of its ability to incorporate new types of visual information.
But Jacobs says the adult brains of colorblind monkeys appear ready to receive new input about color. He says this may be because primates, including humans, have a pathway from the retina that is "almost designed to extract color information."
Robert Shapley, a professor at New York University's Center for Neural Science, says what amazed him was how quickly the monkeys' brains responded once the reprogrammed receptor cells began working.
There was "almost no delay," he says. "That was really striking."
The results bode well for people with colorblindness.
"There's no reason to think that these monkeys and humans are dramatically different in the way they are interpreting color signals from their eyes," Shapley says.
Researchers say this sort of gene therapy may eventually
A Potential But Controversial Fix For Genetic Disease
Newborn monkeys, Mito and Tracker, developed from embryos with transplanted DNA.
EnlargeOregon National Primate Research Center at OHSU
These healthy newborn monkeys, Mito and Tracker, developed from embryos containing transplanted DNA. They are named after the dye 'mitotracker' used for imaging mitochondria in cells.
A fertilized monkey egg undergoes a nucleus transplant.
Oregon National Primate Research Center at OHSU
A fertilized monkey egg undergoes a nucleus transplant.
text sizeAAAAugust 26, 2009
Scientists in Oregon have developed a technique that could be used to prevent certain genetic diseases. They've demonstrated it in monkeys and are anxious to try it in people. The technique raises ethical questions, however, because it makes a permanent genetic change not just in an individual, but in all generations that follow.
The technique involves an unusual set of genes in the human body. Most of our genes are in our chromosomes, which are in the cell's inner sanctum, the nucleus. But 37 human genes are outside the nucleus. They are contained in tiny bodies called mitochondria, which float around in our cells. Mitochondria are the mini power plants for our cells. And mutations in the genes inside mitochondria can cause disease.
Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University are trying to figure out how to treat this class of rare genetic diseases. They've been working with the eggs of rhesus monkeys. If you fix a genetic problem in an egg, you will fix it in all the cells the egg grows into — the whole animal.
"So, basically, we construct this experimental egg, which contains nuclear genes from one female, but mitochondrial genes from another female," he says.
In short, they can remove the nucleus from an egg that has defective mitochondrial genes, and put it into an egg that has healthy mitochondria. So the mother's chromosomes end up in an egg that has healthy mitochondria, albeit from a different female.
The technique worked quite well in monkeys, according to a study the journal Nature has published online. The researchers made this transfer with 15 eggs, fertilized them, and ended up with four baby monkeys.
"So what we showed is these manipulated eggs acted like normal eggs, and most importantly they resulted in births of healthy offspring," Mitalipov says.
The monkeys are only a few months old so far. It will take four or five years before the scientists know whether they are able to reproduce successfully. It could take even longer to notice any long-term health effects. But Mitalipov says he doesn't want to wait that long — he wants to try the technique in people.
To do that, he would need to convince the Food and Drug Administration that the technique is safe. And he will also have to deal with a key ethical issue. Art Caplan at the University of Pennsylvania says the issue is that modifying the genes in an egg doesn't merely affect one individual — the modification ends up in the eggs of the individuals, too.
"It goes on forever, because it's passed on from generation to generation," Caplan says.
This kind of manipulation is called "germ line" therapy, and it's been considered taboo. For one thing, if there are health risks, they will affect multiple generations. For another, it could open the door to genetically engineering a lineage of people with supposedly superior qualities. This is called eugenics, and many people find that repugnant.
"It does breach the principle: no germ line engineering," Caplan says. "It breaches a promise that many geneticists have made, that whatever else, they're not going down that road. I always thought that promise would be difficult to keep. This particular experiment shows why."
Caplan argues the egg manipulation in this case isn't seeking to make an improved person, just a healthy one. And he's OK with that.
But George Annas at Boston University is uneasy — both for ethical reasons and for practical ones.
"I don't think anything should be totally off the table, although this would be pretty extreme," he says. "I would probably have a presumption it shouldn't be done, and the burden of poof would be on the people who propose doing it: that it's safe, and that it's not going to create problems — not just for the children, but for the children's children."
Annas says it will take a lot more than just four apparently healthy baby monkeys to make that case.
Scientists Still Hopeful About Gene Therapy's Promise
by Joe PalcaMarch 8, 2010 www.npr.org
Twenty-five years ago, it seemed as if gene therapy was on the verge of revolutionizing medicine. But that revolution never occurred, and scientists realized that they had been overly optimistic about how quickly they could develop such therapies.
Now, however, there are signs that the field of gene therapy is making definite progress, even if the revolution is still on hold.
The concept of gene therapy is simple. Some diseases are caused by damage to a single gene — for example, cystic fibrosis and hemophilia. Give patients the healthy gene, and in theory, the disease is cured.
From Radical To Reliable: The Rise Of A Medical Treatment
First described as a cancer treatment in the Sept. 12, 1957, issue of the New England Journal of Medicine, bone marrow transplantation did not achieve widespread acceptance until the 1990s. Experts say that gene therapy is on a similar track, and the treatment is on the verge of taking off clinically, much like bone marrow transplantation did in the early 1980s.Source: Appelbaum F. N Engl J Med 2007;357:1472-1475
Credit: Alyson Hurt and Jason Orfanon / NPR
Dr. Mark Kay, who now runs the gene therapy program at Stanford University, says that in the early days of gene therapy, it turned out to be extremely difficult to get healthy genes into the cells that needed them.
"If we saw one cell out of a million, or even 10 million or 100 million, that were genetically modified with the gene therapeutic, we would be excited," he says.
How Gene Therapy Works
It's no simple job to get genes into individual cells, but there is one organism that is extremely good at it: a virus.
"What a virus does is deliver its own genetic material to a cell," says Ken Cornetta, president of the American Society of Gene and Cell Therapy.
A technician at Avigen Inc., a company pursuing cures based on gene and cell therapy, collects re-engineered viruses, called "vectors." Viruses, stripped of their virulence and ability to replicate, are the most common delivery vehicles for healthy DNA.
Inside A Gene Therapy Breakthrough
With one injection of an experimental gene therapy treatment, doctors have significantly improved the sight of people born with a rare congenital vision disorder .Science Friday: Gene Therapy And Blindness
"What we can do in the setting of gene therapy is to re-engineer that virus to allow it to do what it does best, which is deliver genetic material to a cell. But we can also remove the viral genes, and replace them with the genes that we need to deliver to the cell to treat the disease," he says.
But there were problems. When scientists used viruses to insert genes into patients, their immune systems tried to fight off the virus. And then, when the genes did get in, in some cases they switched on other genes that caused cancer, making the cure nearly as bad as the disease.
"The field was in big trouble 10 years ago, says Joseph Glorioso, a researcher and editor of the journal Gene Therapy. "A lot of people were disillusioned — 'Oh this is never going to work, we thought it would be easy,' and all that."
But Glorioso says gene therapists are a stubborn bunch, and despite the setbacks, many researchers kept at it. He says many therapies take a long time to make it from the lab bench to the bedside.
Take bone marrow transplants. They were first attempted in the 1950s, but it wasn't until the 1980s that they began to be used routinely to treat leukemia and other blood disorders.
A Reason To Be Optimistic
The field of gene therapy is now seeing positive results. Scientists have found new ways to modify viruses to make them better at delivering genes, and several studies are showing that the gene therapy can effectively treat an array of disorders.
There's a therapy for a rare immune disorder called ADA deficiency, and more recently scientists at the Children's Hospital of Philadelphia reported dramatic success using gene therapy to treat a rare inherited form of blindness. It was a small study — only 12 subjects.
"All of the subjects showed improvement," says Kathy High, a Howard Hughes Medical Institute investigator and one of the leaders of the study. She says the improvement was greatest for the children in the study.
High says we should expect to hear more success stories in the coming months and years — and not just for rare disorders, but for more common diseases like AIDS and cancer.
"I really do think that the field, you know, after a long labor, is beginning to deliver," says High. "It's a nice time to be working in this field."
Maybe now, scientists' optimism is justified
Rare Disease Treated Using Gene Therapy
by Joe Palca www.npr.orgtext sizeAAANovember 5, 2009
Researchers in France have successfully treated two young boys with a rare but fatal genetic disease. This marks a high point for the field of gene therapy after several well-publicized setbacks.
Brain scans of two boys with ALD. The scans on the left (A) are from a patient who received gene therapy; the one on the right (B) did not. The white areas represent the brain damage caused by the disease. The arrow on the left points to an area that showed some damage, but receded over the course of the therapy. Click on the image to see how the brains progressed over time.
Brain scans of two boys with ALD. The scans on the left (A) are from a patient who received gene therapy; the one on the right (B) did not. The white areas represent the brain damage caused by the disease. The arrow on the left points to an area that showed some damage, but receded over the course of the therapy. Click on the image to see how the brains progressed over time.
Patrick Aubourg leads the French research team. Since 1993, he's been working on a disease called X-linked adrenoleukodystrophy — or ALD. ALD is a devastating neurological disease, incapacitating and ultimately killing people who have it. Many people became familiar with ALD from the 1992 movie Lorenzo's Oil, which featured a young boy affected with this disease.
Viral Vectors
Since ALD is caused by a single gene, it's an ideal candidate for gene therapy. Put the repaired gene back into patient's cells, and that should fix the problem.
Simple in theory, but in practice, it's been extremely difficult. The biggest hurdle has been finding an efficient way to get the repaired gene into the cells of patients. One of the tricks involves attaching the gene to a virus. The virus acts as a vector, inserting the repaired gene into cells.
But the viral vectors can cause their own problems. In one case, another team of French researchers successfully treated several patients with a different single-gene disease, only to find that the vector caused some of the patients to develop leukemia.
Aubourg thinks he has now found a safer virus, and after treating two patients, the results are promising. As he and colleagues report in the Nov. 6 edition of Science, two patients have now been successfully treated.
"I use the term 'treated,' " says Aubourg. "I don't use the term 'cure' — treated. The disease has been arrested, not reversed, really."
But arresting the disease may be enough if the treatment is done before the disease progresses too far.
David Williams of Children's Hospital Boston says Aubourg's technique for getting the repaired gene into a patient's cells is the most efficient yet reported. But it's still not all that efficient.
"They have about 10 to 20 percent of the cells carry the new gene," says Williams. But, he adds, "that's enough, it appears, to arrest the progression of the disease."
Safety Issues
Williams also thinks Aubourg's new viral vector will be safer than others used in the past. Aubourg does not report any problems associated with the vector in his Science paper.
"Having said that, these patients are still only three years or so out from their therapy," says Williams. "So it's still possible that something would evolve, although there's no indication in the molecular analysis that it would evolve."
Other researchers are impressed with the French team's results. Jude Samulski, director of the gene therapy center at the University of North Carolina, says it should change the way ALD is treated.
"It's going to start a flurry of activity," says Samulski. Even though it's a rare disease, he says that at the University of North Carolina, they see a lot of kids with the disease. "And now that we know there's an approach that might work, we'll start trying it. Because if they can't get a bone marrow transplant, they've got nothing."
Bone marrow transplants have been shown to work with ALD patients, but the transplants are risky, and frequently there's no donor available.
Gene Therapy's Coming-Of-Age
Williams says the French results may mean gene therapy is finally coming of age.
"When gene therapy started, there were a lot of predictions that this was going to revolutionize medicine. It's been a long time to actually get it to work in humans"
If the treatment for ALD holds up, it might be the start of that revolution
Examining Gene Therapy As Treatment For Blindness
October 30, 2009Listen to the Story www.npr.org
October 30, 2009Reporting in The Lancet, doctors found success in treating Leber's congenital amaurosis, a rare type of blindness, with gene therapy. Study author Katherine High explains how injecting a gene-carrying virus into the eye has improved vision in a handful of patients.
Copyright © 2009 National Public Radio®. For personal, noncommercial use only. See Terms of Use. For other uses, prior permission required.
IRA FLATOW, host:
This is SCIENCE FRIDAY from NPR News. I'm Ira Flatow.
A blind boy who could read only Braille can now see well enough to read print in a book. How? Via gene therapy. Last year, we spoke with a doctor who was working on treating a certain type of congenital blindness using gene therapy. Katherine High is back to tell us about how the patients are doing today. She's a professor of pediatrics at the University of Pennsylvania School of Medicine, the director of the Center for Cellular and Molecular Therapeutics at Children's Hospital at Philadelphia and Howard Hughes investigator and author of a study in the Lancet, describing the results of the treatment. Welcome back to SCIENCE FRIDAY.
Dr. KATHERINE HIGH (Professor of Pediatrics, University of Pennsylvania School of Medicine; Director, Center for Cellular and Molecular Therapeutics, Children's Hospital): Thank you very much.
FLATOW: Tell us - give us a little bit of up-to-dateness. What happened since the last time we spoke with you?
Dr. HIGH: Well, since the last time we spoke, we have added another nine subjects to the study. So in May of 2008, we reported the results on the first three, and they were all young adults. And in the interim, we've had the opportunity to inject another nine subjects, five of whom were children under the age of 18, and we have seen in all of those individuals improvements in retinal and visual function. And the most interesting finding out of the study, in my opinion, is that the most dramatic improvements were seen in the youngest subjects, particularly those in the range of eight, nine and 10 years old.
So for those individuals, as you discussed at the beginning, there's been a very marked improvement in vision such that children who were using Braille are now, as you said, able to operate in a sighted classroom.
FLATOW: And we also have on our Web site something from your lab, an obstacle course - if you go to sciencefriday.com�
Dr. HIGH: Right.
FLATOW: �where you can see these kids - treated eyes versus the untreated eyes. It's dramatic how well they can get around this obstacle course.
Dr. HIGH: Right, exactly. So in every case, people who come in for the procedure undergo extensive baseline testing. And we identify the eye with the poorer function, and that's the eye that's injected in an effort to preserve the better eye, although sometimes that's a very difficult determination to make. But as you can see on the video on the Web site, two or three months after the vector's been injected, the children do much better with the injected eye, which was formerly the worse eye.
CONAN: Describe for us exactly what you're doing, what the injection is, how it repairs the eye.
Dr. HIGH: Okay, so just first of all from an anatomic standpoint, the injection is going into a space, the sub-retinal space just under the retina. And what your retina basically consists of is a set of cells called the retinal pigment epithelial cells that are nurse cells, basically, for the photoreceptors, and of course, the business part of the retina are the photoreceptors.
And then from a biochemical standpoint, what's really happening in the retina is that it converts a photon of light energy to an action potential that can travel up a nerve and trigger vision.
FLATOW: A little electrical signal.
Dr. HIGH: A little electrical signal. And so in people with this particular variant of Leber's Congenital Amaurosis, they are missing a critical enzyme in that visual pathway. So in other words, the way that that works is when the photon of light strikes the visual pigment in the retina, it causes a chemical change, but eventually the molecule has to be restored. And for that recharging or restoration process, the molecule goes back into the retinal pigment epithelial cells. But if you don't have the enzyme that can recharge that molecule, then the visual cycle is broken.
So all we're doing in this procedure is making an injection, going into those retinal pigment epithelial cells, that gives the person the gene that encodes that missing enzyme.
CONAN: So you inject the gene, and it repairs - it creates that missing enzyme.
Dr. HIGH: Right.
CONAN: And how long does it last for? Is it forever?
Dr. HIGH: Well, that's of course a very important question. In pre-clinical studies that were done by my colleague, Jean Bennett and Al Maguire and others here at the University of Pennsylvania, she has shown that in dogs affected with the same disease, a single injection has lasted for periods up to 10 years. And that's really as long as the animals have been followed.
FLATOW: Right.
Dr. HIGH: So the evidence is that it's a long-lasting effect.
FLATOW: And the fact, when you say it's working better with younger kids, why would it work better the younger you get the kids?
Dr. HIGH: Well, the reason for that is that there are more cells left -remaining, that can be resuscitated by the enzyme. So in other words, if you don't have this enzyme, you eventually start to build up toxic metabolites in these retinal pigment epithelial cells, the nurse cells, and when they start to degenerate, they can't keep up their function of supporting the photoreceptors, and so they start to deteriorate. And this is a slow process that occurs over years. But if you can do the enzyme replacement at an earlier point, then there will be more cells left there to rescue.
FLATOW: And how much, what potential for restoring sight is there? I mean, how much better can the sight really become?
Dr. HIGH: Well, I think the answer to that, at least based on studies in animal models of the disease, is that the earlier you can treat, the better you can come to completely normal function. So I think if you projected what would this product look like eventually, what you would like to be able to do is to treat a child as soon as they're diagnosed and in both eyes.
FLATOW: I've got a question from Second Life from Laura Ginold(ph), who anticipated my next question, and that is, of course we're all going to be wondering what other similar treatments can be used for other vision problems. Can you actually do gene therapy on other retinitis pigmentosa, other kinds of things?
Dr. HIGH: Well, of course, people are working hard on all those kinds of things. And I think that within the next year, within the next 12 months, we will see trials initiated for other retinal disorders. Some of them will be additional inherited diseases, and others will be acquired conditions like macular degeneration. But I think people will try to explore this now as a platform for other diseases. And in addition to things like age-related macular degeneration, other kinds of trials that are already in the planning process - or, you know, getting close to initiation - would be things like X-linked retinal skesis, which is a disease that affects males with diminishing vision in adolescence and early adulthood. Leber heredic optic neuropathy is another disease for which people have trials in the planning stages.
So most of these are rare conditions, but I think that this kind of work paves the way to try to move into somewhat more common causes of inherited retinal degenerative disease.
FLATOW: Because, you know, we haven't heard a lot of success stories about gene therapy. There's a lot of promises, but this seems to be one success story.
Dr. HIGH: Well, you know, Ira, I think if you look across the spectrum of development of new classes of therapeutics, the reality is that the first clinical testing of gene therapy occurred almost 20 years ago, so - 19 years ago to be accurate, and to take something like 20 years to - from the beginning of clinical testing to real, demonstrated success is not really outside the common boundaries for new classes of therapeutics.
So if you think about how long it to develop monoclonal antibody therapeutics - you know, I remember when I was in medical school always reading about how monoclonal antibodies don't work. Now we have lots of different products that are basically monoclonal antibodies.
And similarly for bone marrow transplantation. And so the timelines can seem quite long, but you know, in fact for all new classes of therapeutics, what you see is that things tend to proceed quite slowly at first, as clinical testing reveals problems or issues that have to be taken back to the laboratory to solve, but then as those are worked through, the pace of development tends to accelerate. And I hope that we're coming to that stage in gene therapy. And I think that's probably realistic if you look at other successes that have been reported in the last 12 months. For example, for some severe combined immunodeficiency disorders that leave children at risk for life-threatening infections, you know, there's a very successful report published earlier this year in the New England Journal from a group in Milan. So I think that it is not unreasonable to suspect that we will, I hope, see additional successes in gene therapy going forward.
FLATOW: Ned Perry(ph) writes a tweet about why - how did researchers come up with this solution in the first place? How did they discover this approach? Is the retina a very good place to use this kind of therapy?
Dr. HIGH: Well, I do think it's a - you know, one of the important realizations as the field of gene transfer has developed is that there may be very important constraints on tissues where it's most likely to be successful. And an earlier observation using this type of vector introduced into other tissues - for example, the liver - was that the human immune response could shorten or block expression, but the beauty of the sub-retinal space and the central nervous system, as well - so this applies to some of the observations that have been made in gene therapy trials for Parkinson's Disease, too - these are relatively immuno-privileged sites. So the human immune response cannot come in and attack the transduced cells, or at least not as easily, and that may be an important key to success here.
FLATOW: You have the blood-brain barrier, you're saying?
Dr. HIGH: Yeah, the blood-brain barrier operating in your favor. When you go into something like the retina, you're using very low doses of vector. So you're less likely to trigger the immune response. So all of those factors, I think, probably helped.
FLATOW: And so you'll continue doing this research?
Dr. HIGH: We certainly will.
FLATOW: We'll be - it's exciting, have you back every once in a while and keep following how well you're doing.
Dr. HIGH: Okay, great.
FLATOW: Terrific. Thanks very much, Doctor.
Dr. HIGH: Okay, thank you.
FLATOW: You're welcome.
Dr. HIGH: Bye-bye.
FLATOW: Katherine High is professor of pediatrics at the University of Pennsylvania School of Medicine and director of the Center for Cellular and Molecular Therapeutics at Children's Hospital in Philly and a Howard Hughes investigator.
We're going to take a break, come back and switch gears and talk about the - this is the 40th anniversary of the Internet. Wow, 40 years ago, there was a seminal event, and we actually have one of the guys who was in the room at the time. So stay with us. We'll be right back.
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FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY from NPR News.
Thanks To Gene Therapy, Monkeys See In Full Color
by Jon HamiltonSeptember 17, 2009
Listen to the Story www.npr.org
Dalton, a squirrel monkey, had gene therapy to correct his colorblindness. The image on the left is digitally altered to simulate what the scene would look like to a person (or monkey) with red-green color blindness.
September 17, 2009
Scientists have used gene therapy to achieve full color vision in two squirrel monkeys that were born unable to tell red from green.
The technique could someday be used on people with colorblindness or other vision problems.
All Male Squirrel Monkeys Are Colorblind
The monkeys, named Sam and Dalton, could see only blue and yellow before they were treated.
All male squirrel monkeys are born with this type of color blindness. They lack a receptor in their eyes that would let them see red and green. Female squirrel monkeys do have the receptor and can see the whole spectrum.
Researchers at the University of Washington developed a gene therapy technique to reprogram some of the color receptors in the male monkeys' eyes.
But many scientists were skeptical about the approach, says Jay Neitz, a University of Washington professor of ophthalmology.
"I went out and asked all my neuroscientist friends, 'If I do this in an adult monkey, will this give them color vision?' " Neitz says. "And everyone said, 'Absolutely not.' "
Dalton takes the color vision test. The monkey was trained to find blobs of color hidden in a pattern of dots. He was given a drop of juice every time he got the correct answer.
Reprogramming Color Receptors
The scientists told Neitz that even if the new receptors worked properly, it was unlikely that the monkeys' new eyes would be able to communicate with their old brains. There would be no pathway to carry the information about red and green to the brain, or any circuitry to process it.
Neitz and his team tried the experiment anyway.
Dalton — named after John Dalton, the British scientist who originally described colorblindness — got treated first.
For several months, there was no change. Every day, Dalton tried to win an extra juice reward by searching for a red or green target on a computer screen. And every day he failed.
As time passed, Neitz says he got anxious. But he wasn't surprised. Previous experiments had shown that it took about five months to reprogram a critical mass of receptor cells.
Remarkable Results
Then, at just about the five-month mark, Dalton started hitting the target every time.
"At first we told ourselves, 'You know, maybe he's just guessing really well today or something,' " Neitz says. "But over a few days, it became clear that he wasn't guessing. That floored us."
Later on, the other squirrel monkey, Sam, would have a similar epiphany.
Neitz says both monkeys have seemed pretty pleased with themselves ever since.
"It's just like a kid that goes in, and they don't want to get wrong answers on a test," he says. "They're very happy to be straight-A students now.
Scientists who study color vision are calling the story of Sam and Dalton, which appears in the journal Nature, "dazzling" and "surprising."
Retraining An Adult Brain
Gerald Jacobs, a research professor at the University of California, Santa Barbara, says it's remarkable that the technique worked at all on an adult animal.
Earlier research had shown that, after childhood, the brain loses much of its ability to incorporate new types of visual information.
But Jacobs says the adult brains of colorblind monkeys appear ready to receive new input about color. He says this may be because primates, including humans, have a pathway from the retina that is "almost designed to extract color information."
Robert Shapley, a professor at New York University's Center for Neural Science, says what amazed him was how quickly the monkeys' brains responded once the reprogrammed receptor cells began working.
There was "almost no delay," he says. "That was really striking."
The results bode well for people with colorblindness.
"There's no reason to think that these monkeys and humans are dramatically different in the way they are interpreting color signals from their eyes," Shapley says.
Researchers say this sort of gene therapy may eventually
A Potential But Controversial Fix For Genetic Disease
by Richard HarrisAugust 26, 2009
Listen to the Story www.npr.org
These healthy newborn monkeys, Mito and Tracker, developed from embryos containing transplanted DNA. They are named after the dye 'mitotracker' used for imaging mitochondria in cells.
A fertilized monkey egg undergoes a nucleus transplant.
text sizeAAAAugust 26, 2009
Scientists in Oregon have developed a technique that could be used to prevent certain genetic diseases. They've demonstrated it in monkeys and are anxious to try it in people. The technique raises ethical questions, however, because it makes a permanent genetic change not just in an individual, but in all generations that follow.
The technique involves an unusual set of genes in the human body. Most of our genes are in our chromosomes, which are in the cell's inner sanctum, the nucleus. But 37 human genes are outside the nucleus. They are contained in tiny bodies called mitochondria, which float around in our cells. Mitochondria are the mini power plants for our cells. And mutations in the genes inside mitochondria can cause disease.
Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University are trying to figure out how to treat this class of rare genetic diseases. They've been working with the eggs of rhesus monkeys. If you fix a genetic problem in an egg, you will fix it in all the cells the egg grows into — the whole animal.
"So, basically, we construct this experimental egg, which contains nuclear genes from one female, but mitochondrial genes from another female," he says.
In short, they can remove the nucleus from an egg that has defective mitochondrial genes, and put it into an egg that has healthy mitochondria. So the mother's chromosomes end up in an egg that has healthy mitochondria, albeit from a different female.
The technique worked quite well in monkeys, according to a study the journal Nature has published online. The researchers made this transfer with 15 eggs, fertilized them, and ended up with four baby monkeys.
"So what we showed is these manipulated eggs acted like normal eggs, and most importantly they resulted in births of healthy offspring," Mitalipov says.
The monkeys are only a few months old so far. It will take four or five years before the scientists know whether they are able to reproduce successfully. It could take even longer to notice any long-term health effects. But Mitalipov says he doesn't want to wait that long — he wants to try the technique in people.
To do that, he would need to convince the Food and Drug Administration that the technique is safe. And he will also have to deal with a key ethical issue. Art Caplan at the University of Pennsylvania says the issue is that modifying the genes in an egg doesn't merely affect one individual — the modification ends up in the eggs of the individuals, too.
"It goes on forever, because it's passed on from generation to generation," Caplan says.
This kind of manipulation is called "germ line" therapy, and it's been considered taboo. For one thing, if there are health risks, they will affect multiple generations. For another, it could open the door to genetically engineering a lineage of people with supposedly superior qualities. This is called eugenics, and many people find that repugnant.
"It does breach the principle: no germ line engineering," Caplan says. "It breaches a promise that many geneticists have made, that whatever else, they're not going down that road. I always thought that promise would be difficult to keep. This particular experiment shows why."
Caplan argues the egg manipulation in this case isn't seeking to make an improved person, just a healthy one. And he's OK with that.
But George Annas at Boston University is uneasy — both for ethical reasons and for practical ones.
"I don't think anything should be totally off the table, although this would be pretty extreme," he says. "I would probably have a presumption it shouldn't be done, and the burden of poof would be on the people who propose doing it: that it's safe, and that it's not going to create problems — not just for the children, but for the children's children."
Annas says it will take a lot more than just four apparently healthy baby monkeys to make that case.
On-Demand Body Parts: Inventing The Bio-Printer
March 14, 2010Listen to the Story
All Things ConsideredA medical invention currently in development may one day be able to create new organs, right there in the hospital. The 3-D bio-printer takes cells from a patient's failing organ and "prints out" a new organ — almost like a 3-D ink-jet printer. Guy Raz explains how the device works with the man who developed the prototype, Gabor Forgacs.
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GUY RAZ, host:
We're back with ALL THINGS CONSIDERED from NPR News. I'm Guy Raz.
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RAZ: Your typical ink-jet printer can produce a lot of things, from documents to decent photos, but a scientist from the University of Missouri thought the mechanism behind them could actually do something a lot more complicated.
Gabor Forgacs thinks they could print our organs, as in human organs, and he's built a high-tech printer to do just that. Here's how it works.
Dr. GABOR FORGACS (Scientist, University of Missouri): You scoop out cells from the patient.
RAZ: So if you want a new heart, some cardiac cells, if you want a new stomach, some stomach cells, and so on. And he takes this cluster of cells.
Dr. FORGACS: That may contain anything between 10 to 30,000 cells.
RAZ: And he mixes it into a liquid, something Gabor Forgacs calls bio-ink, and just like in the printer connected to your computer, this bio-ink shoots out of a cartridge. And it's printed, dot by dot, onto a gelatin-like sheet of paper, or what he calls bio-paper.
Dr. FORGACS: It is a material that mimics what we have in our body between the organs, that surrounds the organs. It's called the extracellular matrix. Cells love it.
RAZ: And when placed together on the bio-paper, the bio-ink, those cell clusters, starts to fuse and form shapes, but at this point, the printout is still two-dimensional. So another sheet of bio-paper is layered right on top with another cluster of bio-ink.
The principle is a little like building a skyscraper. You start with the bottom level, then build up.
Dr. FORGACS: Then imagine that comes the second story, and then comes the third story.
RAZ: And on and on until you have something that starts to look like an organ. Forgacs' printer is connected to a computer that then directs how those layers should be shaped, a predesigned scheme a little like paint-by-numbers.
Dr. FORGACS: And that scheme you can get by taking an X-ray or a CT image of the organ, and you try to repeat the outline of the organ. Of course, it's very complicated, but we have now the precision to place the cells according to this scheme and end up with a three-dimensional object.
RAZ: The layers of bio-paper between the cell clusters eventually melt away as the cells start to fuse.
Dr. FORGACS: They fuse both in the plane, so a circle will turn into a little doughnut-shaped object, and they also fuse in the third dimension. So imagine that if you put circular arrangements on top of each other, the stories are like circles, then eventually they fuse and you get a cylinder.
RAZ: And those cylinders are what Dr. Forgacs is on the verge of perfecting right now. He and his team are close to printing out human blood vessels.
Hearts and livers are still a ways away. The first step is to implant these printed blood vessels inside a human body. But how would those printed organs know how to function?
Dr. FORGACS: When we are in embryo, you can ask the same question: how does the embryo know how to form those complicated organs? These are the product of evolutions of many, many millions of years. They know what to do.
RAZ: Now, whether Gabor Forgacs' science can mimic evolution is still a question. The 3-D bio-printer is a long way from showing up at your local hospital, but he thinks human testing can actually begin fairly soon.
Dr. FORGACS: In the next five years there will be a great breakthrough.
RAZ: In the meantime, Forgacs and his team at the University of Missouri are experimenting on rats. They've already implanted some with nerve grafts created with the bio-printer.